A dopaminergic eye–brain correspondence in Parkinson's disease: the substantia-nigra molecular signature localizes to the inner- retinal neurons
A dopaminergic eye–brain correspondence in Parkinson's disease: the substantia-nigra molecular signature localizes to the inner- retinal neurons
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Publication status: preprint
A plain-language reading has not been prepared for this paper yet.
Original abstract
Abstract Background Visual and retinal changes are common in Parkinson's disease (PD), yet the molecular link between the diseased substantia nigra and the eye is unclear. We tested whether the dopaminergic programme that degenerates in the Parkinsonian substantia nigra is expressed in the retinal dopaminergic system, using only public data. Methods We integrated six substantia-nigra microarray cohorts (64 patients, 54 controls) to define a cross-cohort differential-expression signature, evaluated its cross-cohort classification performance by leave-one-dataset-out machine learning, and tested its localization and dopaminergic co-expression in independent bulk and single-nucleus human retina atlases using expression-weighted cell-type enrichment and permutation tests. Independent support was sought through Parkinson's disease genome-wide association study gene enrichment, Human Protein Atlas protein-level data, an independent substantia-nigra cohort, an independent single-nucleus atlas, and an independent retina atlas. Results The differentially expressed genes were uniformly down-regulated and dominated by dopaminergic and synaptic transcripts (DDC, SLC6A3, SV2C, KCNJ6, AGTR1). The signature classified disease across cohorts (leave-one-dataset-out AUROC 0.74; permutation P = 0.02), whereas a whole-blood signature did not generalize. In an independent retinal atlas it localized to inner-retinal neurons, most strongly to retinal ganglion and amacrine cells; this persisted after removing all dopaminergic genes and against a null restricted to neuronal genes, with photoreceptors depleted, arguing against a circular or generic neuronal effect. The genes also co-expressed with retinal dopamine markers above background. The signature's direction replicated in a held-out nigral cohort (96% concordant) and, on single-nucleus data, concentrated in dopaminergic neurons (Cliff's delta = 0.89); it was enriched for established PD risk genes; and its retinal co-expression and localization reproduced in a separate atlas. Conclusions Because the retinal datasets lack PD donors, these analyses establish molecular correspondence and cell-type localization rather than a disease-state change. They nonetheless give the retinal phenotype of PD a defined molecular substrate, the inner-retinal neurons carrying the dopaminergic programme, and nominate dopamine-sensitive retinal readouts as mechanistically grounded candidates for future study.